Epistemological distinctions in synthetic biology
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Epistemological distinctions
in synthetic biology
1
Four levels of epistemological
p g
distinction
•Synthetic biology as a distinctive whole
•Synthetic biology’s streams of practice
•Synthetic biology in relation to other
disciplines
•Synthetic biology in relation to scientific
practice and knowledge in general
2
1. Synthetic biology’s distinctions
•Engineering as a response to parts
lists: ‘The
The overwhelming physical details
of natural biology … must be organized
and recast via a set of design rules that
hide information and manage complexity’
(Keasling, 2008)
•Engineering becomes a shaper of
techniques, data
data-gathering
gathering and
research questions (Brent, 2000)
•Three Rs
•Rationality
•Robustness
•Reliability Lazebnik, 2002
3
Engineering in
synthetic biology
•Analogize
•Synthesize
•Mechanicize
•Kludge
4
a. Analogizing practice
5Analogizing components and levels
Adrianantoandro et al., 2006 67
Disanalogies
•Evolution is not design
•Connections are unknown
•Complexity is not maskable
•Abstraction is limited
8Modules
•Separable
•Standardizable
•Interchangeable
•Stable/predictable
‘Our
Our results indicate that partition
of a network into small modules
… could in some cases be
misleading, as the behaviour of
the module is affected to a large
extent
t t by
b the
th restt off the
th network
t k
in which they are embedded’
(Isalan et al.,
al 2008)
9Anti disanalogizing
Anti-disanalogizing
Disanalogy 1: ‘The
The cell is too complex for
engineering approaches.’
No, because:
(a) biology can’t handle simple systems so it won’t
be better at handling complex systems
(b) engineers are undeterred by complex systems
because they have formal languages and
computational power.
(Lazebnik, 2002)
10Disanalogy 2: ‘Engineering approaches are not
applicable
li bl tot cells
ll b
because [[cells]
ll ] are ffundamentally
d t ll
different from the objects studied by engineers.’
No. ‘This is vitalism.’ There are, in fact, deep similarities
between living g systems
y and other designed
g systems.
y
Disanalogy 3: ‘We know too little about cells
t analyse
to l them
th iin th
the way engineers
i
analyse their systems.’
No. We know enough to put together
formal models and find out at least the
processes that are missing in our existing
explanations.
(Lazebnik, 2002)
11b. Synthesizing
y g
Analysis = deconstruction, individualization of parts;
Oft
Often linked
li k d to
t ‘di
‘discovery-oriented’
i t d’ approaches h
Synthesis = fabrication/construction
fabrication/construction, integration;
often linked to design-oriented approaches
In practice, synthetic biology is as
analytic as it is synthetic
synthetic, but a
special claim is made for an
p
epistemologygy of ‘constructing’g or
making as the real source of
knowledge.
i
i.e., k
knowledge
l d = making
ki
12c. Mechanicize
Put things together
in a rational way
y&
make them work!
The art of
combining
re/constructed
parts using circuit
g
analogies into
obviously
functioning devices.
Why is it an ‘art’?
Two reasons
13i)) Not copying,
py g, but recreating
g
‘Much simpler, less reliable than natural clock
circuits,
i i but prooff off principle
i i ffor a synthetic
i
approach’ (Sprinzak & Elowitz, 2005).
14ii) Coping with heterogeneity
•Fluctuation of processes within cells
•Variability between ‘identical’ cells
•Variation in general, including standards: ‘The nicest
thing about standards is that there are so many of
them to choose from’ (Ken Olsen [founder of Digital
Equipment Corp] 1977)
15d. Kludging
Kludge = workaround solution (klumsy,
lame ugly,
lame, ugly dumb,
dumb but good enough),
enough)
also known as ‘kluge’
16Kludging as a highly creative and effective process Debugging designed circuitry is essential ‘Indeed, Indeed, testing, debugging, and maintenance reportedly account for fourth-fifths of all software development costs’ (Joachim & Maurer, 2007) 17
Biological kludge (fictional)
18‘Synthetic biology, with its focus on elucidating and
harnessing design principles of living systems
systems, aims to
tackle these problems [of shaping the biological
world to meet our needs]. ] But unlike other
engineering disciplines, synthetic biology has not
developed to the point where there are scalable and
reliable
i approaches to fifinding
i solutions.
i
Instead, the emerging applications are most often
Instead
kludges that work, but only as individual
special
p cases. Theyy are solutions selected
for being fast and cheap and, as a result,
they are only somewhat in control’
(A ki and
(Arkin d Fl
Fletcher,
t h 2006)
2006).
19Pragmatics of kludging
Kludging
g g is the connection point
p of
biology, engineering and evolution.
•Evolution
E l ti constantly
t tl produces
d kl
kludges:
d th
the
history of evolution is a history of kludging
•Biologists kludge all the time in experiments
•Engineers of all types kludge to make things work
Kludging is an inescapable aspect of a pragmatic
approach to knowledge and construction.
Synthetic biology is in many respects anti-kludge: it
wants nature and engineering to be elegant and
efficient.
202. Distinctive streams
of practice in
synthetic biology
What do these
distinctions imply for a
general
ge e a understanding
u de s a d g o of
synthetic biology?
21a. DNA-based device construction
•DNA synthesis upwards
•Standardization,, decoupling,
p g, abstraction
•De-kludging biology
22b. Genome-driven cell engineering
•Streamlining and modularizing genomes
•Genome as a dekludgable, relocatable module
23c. Protocell creation
•Micelles, lipid self-
assembly,
bl vesicles
i l with
ith
ribozymes
•Many allowances for
kludging, although
keen to minimize
excess kludges
24Protocells & minimal cells
Top-down and bottom-up
approaches
25LUCA: the original
kludge?
26Knowledge-making dynamics in synthetic biology:
Replacing/displacing kludges with rationally determined,
highly predictable systems
(O’Malley et al. 2008)
274 Disciplinary relationships
4.
Approach tool
Approach, tool, field
field, discipline
discipline, application?
28‘3 pillars of synthetic biology in Europe’
•Disciplinary nexus?
•Discipline sui generis?
•Toolbox?
29Systems and Synthetic Biology Institute
Imperial College London
Invisibly absorbed to established disciplines & approaches?
30•Is
I synthetic
th ti bi
biology
l a
discipline?
•What
What does discipline
mean now?
•What are the
characteristics of new
disciplines?
•Have
H synthetic
th ti (and
( d
systems) biology given
rise to new
understandings of
‘discipline’?
31Synthetic & systems biology
Two sides of the same coin:
‘Fundamentally
Fundamentally different but
complementary outlooks’ (Koide
et al., 2009)
Systems biology = formal
abstractions
bt ti
Synthetic biology = instantiated
mechanisms
Is systems biology knowledge-
driven and synthetic biology
application driven?
application-driven?
BBSRC
32Synthetic biology applications
Genomics (data) enables systems biology (models)
enables synthetic biology (practical achievements)?
33Metabolic engineering
‘Metabolic engineering typically involves the
exploitation of the whole cell. It also has to
cope with a very high complexity that is
typically not amenable to rational analysis. In
other words,
words it has often relied on “tinkering”
rather than rational “design-based”
engineering, frequently leading to only minor
re-engineering of cellular properties’ (European
Commission report, 2005).
34Tyo et al., 2007 35
‘Metabolic engineering generally
requires more than simply throwing
enzymes together in a cell. Achieving
a synthetic
y g
goal ((e.g.,
g , a strain that
produces a particular product)
requires the management of complex
metabolici and regulatory processes.
In pursuit of this goal
goal, one cannot help
but learn about metabolism and its
emergent
g behaviours,, including
g the
regulation of metabolism and the
extent to which enzymes drawn from
various
i sources can b be combined
bi d
independently. So, synthesis drives
discovery and learning
learning’ (Benner and
Sismour, 2005).
364. Synthetic biology and knowledge-making
Richard Feynman:
‘What I cannot create,, I do not understand'
(1988, last blackboard note)
37‘Naturally, one can
never be sure that all
the bugs are out, and,
for some,, the fix may
y
not have addressed
the true cause’
(Feynman, 1986,
Appendix F, Rogers
Report).
Report)
38Epistemological distinctions
•Rational ordering versus untidy
making-do
g
•‘Pure’ engineering versus
kl d i
kludging
•Disciplinary rhetoric versus
technical achievements (and
failings)
g)
•Causal knowledge versus
practical
ti l construction
t ti
39Concluding questions
Can synthetic biology work within these
tensions or does it need to resolve them?
Does synthetic biology need a special
epistemological
it l i l and d di
disciplinary
i li status
t t iin
order to deliver its promises?
40Acknowledgements
Many thanks for
gg
suggestions and
comments to Sabina
Leonelli, John Dupré and
th audience
the di att th
the ENS
workshop, ‘Historical &
Philosophical Foundations
of Synthetic Biology’. The
research for this project
p j
was funded by the ESRC-
funded centre, Egenis, at
th University
the U i it off Exeter
E t
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